The present invention relates to aminopyrrole compounds and methods for preparing and using the same.
TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Arend, W. P. Arthritis and Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin""s disease (see., Benharroch, D.; et. al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer""s disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Maini, R. N.; et. al. APMIS. 105(4): 257-263, (1997); Feldmann, M., J. of the Royal College of Physicians of London 30(6): 560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology 156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al. Clin. and Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. and Exp. Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., Cooper, A. L., et. al. Am. J. of Physiology 267(6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al. J. of Neuroimmunol. 72(2): 163-168, (1997)) and periodontal diseases.
Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammation and have positive therapeutic outcomes. It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((see., Lee, J. C., et al. Nature. 372 (6508): 739-46, (1994)). Compounds that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.
It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.
One aspect of the present invention provides an aminopyrrole compound of the formula: 
a prodrug, individual isomer, a mixture of isomers or a pharmaceutically acceptable salt thereof and methods for preparing or using the same, wherein
each of Ar1 and Ar2 is independently optionally substituted aryl; and
each of R1 and R2 is independently hydrogen, alkyl or a nitrogen protecting group.
Another aspect of the present invention provides a method for producing an aminopyrrole compound of the formula: 
said method comprising forming an aminopyrrole ring system by contacting a cyano compound of the formula: 
with an arylamine compound of the formula Ar2xe2x80x94NH2 under conditions sufficient to produce the aminopyrrole compound of Formula I,
wherein
each of Ar1 and Ar2 is independently optionally substituted aryl.
Another aspect of the present invention provides a composition comprising a therapeutically effective amount of a compound of Formula I and an excipient.
Still another aspect of the present invention provides a method for inhibiting p38 MAP kinase in a cell comprising administering a compound of Formula I to the cell comprising p38 MAP kinase.
Yet another aspect of the present invention provides a method for treating a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration to the mammal a therapeutically effective amount of a compound of Formula I.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon moiety of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a moiety xe2x80x94OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.
xe2x80x9cAcylxe2x80x9d means a moiety xe2x80x94C(O)R where R is hydrogen, alkyl, haloalkyl, or heteroalkyl, e.g., acetyl, trifluoroacetyl, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like.
xe2x80x9cHalidexe2x80x9d means fluoride, chloride, bromide, or iodide.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl moiety as defined above, having one or more, preferably one, two or three, substituents selected from xe2x80x94NRaRb, xe2x80x94ORc wherein Ra, Rb and Rc are independently of each other hydrogen, alkyl, or the corresponding protecting group. Representative examples include, but are not limited to, hydroxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, and the like.
xe2x80x9cHeteroalkoxyxe2x80x9d means a moiety xe2x80x94OR where R is heteroalkyl group as defined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2,3-dihydroxy-1-methylpropoxy, 2-aminoethoxy, and the like.
xe2x80x9cOptionally substituted arylxe2x80x9d means an aryl ring as defined above, which is optionally substituted independently with one or more, preferably one or two, substituents selected from alkyl, alkoxy, heteroalkyl, heteroalkyl, halide, cyano, acyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently selected from hydrogen, alkyl or acyl), xe2x80x94NHCOR (where R is alkyl),xe2x80x94NRS(O)nRxe2x80x2 (where R is hydrogen or alkyl, n is an integer from 0 to 2 and Rxe2x80x2 is hydrogen, alkyl or heteroalkyl), xe2x80x94NRS(O)nNRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl, n is an integer from 0 to 2 and Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nNRRxe2x80x2 (where n is an integer from 0 to 2 and R and Rxe2x80x2 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94COOR, -(alkylene)COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 or -(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl).
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl which is optionally substituted independently with one or more, preferably one or two, substituents selected from alkyl, alkoxy, heteroalkyl, heteroalkyl, halide, cyano, acyl, xe2x80x94NRRxe2x80x2 (where R and R are independently selected from hydrogen, alkyl or acyl), xe2x80x94NHCOR (where R is alkyl), xe2x80x94NRS(O)nRxe2x80x2 (where R is hydrogen or alkyl, n is an integer from 0 to 2 and Rxe2x80x2 is hydrogen, alkyl or heteroalkyl), xe2x80x94NRS(O)nNRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl, n is an integer from 0 to 2 and Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), xe2x80x94S(O)nNRRxe2x80x2 (where n is an integer from 0 to 2 and R and Rxe2x80x2 are independently hydrogen, alkyl or heteroalkyl), xe2x80x94COOR, -(alkylene)COOR (where R is hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3 or -(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl).
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9caryl group optionally mono- or di-substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
When referring to a chemical reaction, the terms xe2x80x9ctreatingxe2x80x9d, xe2x80x9ccontactingxe2x80x9d and xe2x80x9creactingxe2x80x9d are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
xe2x80x9cTherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
One aspect of the present invention provides 
a prodrug, individual isomer, a mixture of isomers or a pharmaceutically acceptable salt thereof and methods for preparing or using the same, where Ar1, Ar2, R1 and R2 are those defined above.
Preferably, R1 and R2 are hydrogen.
Preferably, Ar2 is an optionally substituted phenyl, more preferably a halide substituted phenyl, and most preferably 4-halophenyl, particularly 4-fluorophenyl.
Preferably, Ar1 is selected from the group consisting of phenyl, alkoxy substituted phenyl, hydroxy substituted phenyl and heteroalkoxy substituted phenyl. More preferably, Ar1 is selected from the group consisting of phenyl, 3-methoxyphenyl, 3-hydroxyphenyl, and 3-(2,3-dihydroxypropoxy)phenyl.
In one embodiment of the present invention, R1 and R2 are hydrogen and Ar2 is optionally subsituted phenyl.
In another embodiment, R1 and R2 are hydrogen and Ar2 is a halide substituted phenyl, preferably 4-fluorophenyl.
Yet in another embodiment, R1 and R2 are hydrogen, Ar2 is 4-fluorophenyl, and Ar1 is selected from the group consisting of phenyl, alkoxy substituted phenyl, hydroxy substituted phenyl and heteroalkoxy substituted phenyl. Preferably Ar1 is heteroalkoxy substituted phenyl. More preferably, Ar1 is 3-(2,3-dihydroxypropoxy)phenyl.
Still yet in another embodiment, R1 and R2 are hydrogen, Ar2 is 4-fluorophenyl, and Ar1 is phenyl, 3-methoxyphenyl, 3-hydroxyphenyl or 3-(2,3-dihydroxypropoxy)phenyl.
In another embodiment of the invention, R1 and R2 are hydrogen and Ar1 is optionally substituted phenyl. Preferably, Ar1 is phenyl, alkoxy substituted phenyl, hydroxy substituted phenyl or heteroalkoxy substituted phenyl. Preferably Ar1 is heteroalkoxy substituted phenyl. More preferably, Ar1 is 3-(2,3-dihydroxypropoxy)phenyl. Within this embodiment, Ar2 is preferably halide substituted phenyl, preferably 4-fluorophenyl.
Combinations of the preferred groups described above also form other preferred embodiments. Thus, for example, preferred substituents R1 and R2 are also preferred substituents of compounds having preferred substituents Ar1 and/or Ar2.
The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Furthermore, as stated above, the present invention also includes all pharmaceutically acceptable salts of those compounds along with prodrug forms of the compounds and all stereoisomers whether in a pure chiral form or a racemic mixture or other form of mixture.
The compounds of Formula I are capable of further forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, or example, Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977, 66, 1-19).
The acid addition salts of the basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts can be formed with metal ions or amines, such as alkali and alkaline earth metal ions or organic amines. Examples of metal ions which are used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al , xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977, 66, 1-19).
The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Exemplary compounds of the present invention are shown in Table 1 below:
Preparation of Compounds of Formula I
Compounds of the present invention can be made by the methods described below. The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., U.S.A), Bachem (Torrance, Calif., U.S.A), Emka-Chemie, or Sigma (St. Louis, Mo., U.S.A) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be readily apparent to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
In one embodiment, Ar2 is 4-fluorophenyl.
In another embodiment, Ar2 is 4-fluorophenyl and Ar1 is alkoxy substituted phenyl.
In yet another embodiment, Ar2 is 4-fluorophenyl and Ar1 is alkoxy substituted phenyl, and the method further comprises converting the alkoxy substituent to a hydroxy substituent by contacting the aminopyrrole compound of Formula I with a Lewis acid under conditions sufficient to produce the aminopyrrole compound of Formula I wherein Ar1 is a hydroxy substituted phenyl.
Still in another embodiment, the method further comprises alkylating the hydroxy group of Ar1 by contacting the aminopyrrole compound of Formula I, wherein Ar1 is a hydroxy substituted phenyl, with a heteroalkyl compound comprising a leaving group under conditions sufficient to produce the aminopyrrole compound of Formula I, wherein Ar1 is a heteroalkoxy substituted phenyl.
Yet still in another embodiment, the cyano compound of Formula II is produced by contacting an aroyl acetonitrile derivative of the formula: 
with a 3-haloacetylpyridine of the formula: 
in the presence of a base under conditions sufficient to produce said cyano compound of Formula II, wherein
Ar1 is optionally substituted aryl; and
X is a leaving group.
One particular method for producing compounds of Formula I comprises forming an aminopyrrole ring system by contacting a cyano compound of the formula: 
with an arylamine compound of the formula Ar2xe2x80x94NH2 under conditions sufficient to produce the aminopyrrole compound of Formula I, where Ar1 and Ar2 are those defined above. The aminopyrrole ring forming reaction is typically an acid catalyzed cyclization reaction. Preferably, the acid is a strong acid having pH of about 2 or less. Suitable acid catalysts include inorganic acids, such as sulfuric acid, phosphoric acid, HCl, HBr, HI, as well as Lewis acids such are AlCl3, BBr3, BCl3 and the like. It should be appreciated that when a proton source is available Lewis acids can also generate inorganic protic acid which can also catalyze the cyclization reaction.
The cyclization is generally carried out in a polar solvent such as ethanol, isopropanol and the like. The cyclization reaction temperature depends on a variety of factors including the particular acid catalyst utilized, reaction solvent, reactivity of the starting material, etc. Typically, the cyclization reaction temperature is at least about 80xc2x0 C. In practice, the cyclization reaction is carried out under the refluxing conditions of the reaction solvent.
The cyclization reaction time also depends on a variety of factors such as those described above including the reaction temperature. Generally, however, the cyclization reaction time is at least about 8 hrs under refluxing condition. Typically, the cyclization reaction time is from about 6 hrs to about 16 hours.
The cyano compound of Formula II can be readily prepared by contacting an aroyl acetonitrile derivative of the formula: 
with a 3-haloacetylpyridine of the formula: 
in the presence of a base under conditions sufficient to produce the cyano compound of Formula II, where Ar1 is that defined above and X is a leaving group such as halide, preferably bromide or chloride. Suitable bases for the substitution reaction typically are none nucleophilic bases. Preferably, the base is sufficiently strong enough to deprotonate the aroyl acetonitrile derivative of Formula III. Suitable bases include metal hydrides, metal tert-butoxides and the like. Because a strong base is typically used, the initial deprotonation reaction between the base and the aroyl acetonitrile derivative of Formula III is an exothermic reaction. As such, the reaction temperature is generally kept at about 0xc2x0 C. or less. Typical reaction solvent is an aprotic solvent, such as tetrahydrofuran, and diethyl ether.
Methods of preparing compounds of Formula I can further include modifying the aryl group Ar1 or Ar2. For example, when the aryl group Ar1 contains a substituent, methods of the present invention can include replacing or modifying the substituent on the aryl group. This is particularly applicable where Ar1 is substituted with one or more of amino, carbonyl, hydroxy and alkoxy groups. When Ar1 is substituted with an alkoxy group, the alkoxy group can be converted to a hydroxy group by contacting the compound of Formula I with a Lewis acid. Suitable Lewis acids include those described in Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1999, which is incorporated herein by reference in its entirety.
The free hydroxy group can then be substituted (e.g., alkylated) with a desired substituent. For example, by contacting the hydroxy group with a heteroalkyl compound comprising a leaving group provides an aminopyrrole compound of Formula I, where Ar1 is a heteroalkoxy substituted phenyl.
Utility, Testing, and Administration
Utility
Compounds of the present invention have a wide variety of pharmaceutical activities. For example, present inventors have found that compounds of the present invention are p38 MAP kinase inhibitors. Thus the compounds are useful for the treatment of inflammatory diseases, particularly arthritis.
Therefore, compounds of the present invention are useful in the treatment of a disease which is mediated by p38 MAP kinase, including rheumatoid arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, toxic shock syndrome, endotoxic shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative colitis, pyresis, Alzheimer""s and Parkinson""s diseases.
Testing
The ability of the compounds of the present invention to inhibit p38 MAP kinase was demonstrated by the in vitro assay described in Example 4. The ability of the compounds of the present invention to inhibit the release of TNF-xcex1 was demonstrated by the in vitro and the in vivo assays described in detail in Examples 5 and 6, respectively. The anti-inflammatory activity of the compounds of this invention can be determined utilizing adjuvant induced arthritis in rats assay described in Example 7.
Administration and Pharmaceutical Compositions
In general, the compounds of this invention are administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, typically depends on numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of the present invention can range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 1-30 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 70 mg to 2.1 g per day.
In general, compounds of the present invention are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 3.